Method of Optimizing the treatment of Proliferative Diseases Mediated by the Tyrosine Kinase Receptor KIT with Imatinib

ABSTRACT

The invention relates to a method of treating proliferative diseases mediated by the tyrosine kinase receptor KIT, in particular GIST, in a human patient population.

The present invention relates to a method of treating proliferativediseases mediated by the tyrosine kinase receptor KIT, in particulargastro-intestinal stromal tumors (GIST), in a human patient population.

GIST are uncommon visceral sarcoma that arise predominantly in thegastrointestinal tract. GIST are the most common subtype of GI sarcomas,which also include leiomyosarcomas, liposarcomas and other more rarehistologic subtypes. GIST have been reported to represent about 3% ofall malignant tumours. GIST are most common in the stomach (60 to 70%),followed by small intestine (20-30%).

Recent advances in molecular and immunohistochemical analysis of GISThave identified that GIST cells are positive for CD117, a cell surfaceantigen localised on the extracellular domain of the trans-membranetyrosine kinase receptor KIT, the protein of the proto-oncogene c-KITand receptor for stem cell factor. Upon binding its ligand, stem cellfactor, KIT forms a dimer that is autophosphorylated and activatessignaling cascades that lead to cell growth. Mutations that lead to anactivated form of KIT, especially forms that are activated independentlyof its ligand, are known and are believed to play a role in certainproliferative diseases, such as mast cell diseases, like mastocytosis,particularly systemic mastocytosis, acute myelogenous leukemia, GIST,sinonasal NK/T-cell lymphoma, seminomas and dysgerminomas. It ishypothesized that virtually all malignant GIST harbour mutations ofc-KIT as the driving factor of this disease, resulting in constitutiveactivation of KIT associated with the signal transduction pathway forcell division and tumour growth. KIT overexpression is determined byimmunohistochemistry, which is performed in standard practice.

The present invention relates to a method for minimizing or avoiding theissues of tolerability, lack of efficacy and the risk of relapse inhuman patients suffering from a proliferative disease mediated by thetyrosine kinase receptor KIT. The invention is based on the finding thatthe treatment of a proliferative disease, which is mediated by thetyrosine kinase receptor KIT, comprising the administration of a KITinhibitor or a pharmaceutically acceptable salt thereof to a patientsuffering from such proliferative disease can be optimized by adjustingthe dose of the KIT inhibitor or a pharmaceutically acceptable saltthereof applied to an individual patient in a manner that a specificminimum plasma trough level (Cmin) of the KIT inhibitor is achieved ineach single patient. It was found that an individual adjustment for eachpatient is often required in view of high patient intervariability ofthe Cmin values after administration of KIT inhibitor to each patient.

The term “proliferative disease mediated by the tyrosine kinase receptorKIT” as used herein should include mast cell diseases, such as mast cellleukemia and systemic mastocytosis, acute myelogenous leukemia (AML),GIST, seminomas, dysgerminomas and metastatic melanoma. The term“proliferative disease mediated by the tyrosine kinase receptor KIT”means especially the proliferative disease systemic mastocytosis,particularly aggressive systemic mastocytosis and GIST, morespecifically GIST.

The term “KIT inhibitor” as used herein means a therapeutically activecompound such as a small organic molecule or an antibody, which inhibitsthe activity of the tyrosine kinase receptor KIT, more specifically wildtype KIT and certain KIT mutations as defined below. Preferably, the KITinhibitor inhibits preferably KIT harboring activating mutations.

In one embodiment, the KIT inhibitor employed in the present inventionis Imatinib, which has the structure of formula (I),

hereinafter “Compound (I)”, or a pharmaceutically acceptable saltthereof. Imatinib is a tyrosine kinase inhibitor that selectivelyinhibits wild type KIT and certain KIT mutations. In February 2002 themesylate salt ofN-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine(Imatinib mesylate, STI571, Glivec®) was approved by the FDA for thetreatment of adult patients with CD117 positive unresectable and/ormetastatic malignant GIST.

In another embodiment, the KIT inhibitor employed in the presentinvention is Nilotinib or a pharmaceutically acceptable salt thereof.Nilotinib is a tyrosine kinase inhibitor that selectively inhibits KIT.In 2007 the monohydrochloride monohydrate salt of4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-phenyl]benzamide(Nilotinib monohydrochloride monohydrate, Tasigna®), which has thestructure (II), hereinafter “Compound (II)”,

was approved by the FDA for the treatment of CML for patients who areresistant or intolerant to existing therapies, including treatment withGlivec®. The compound of formula (II) and the process for itsmanufacture are disclosed in U.S. Pat. No. 7,169,791, which is herebyincorporated into the present application by reference.

Mutations that lead to an activated form of KIT as referred to hereininclude, but are not limited to D816F, D816H, D816N, D816Y, D816V,K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558,Del VV559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K,N822H, Y823D, Y823C and T670I.

The present invention provides for the first time an individualizedtreatment schedule for single patients suffering from a proliferativedisease mediated by the tyrosine kinase receptor KIT based on a Cminlower threshold which was shown to be correlated with an increasedoverall response (OR) rate and an increased time to progression (TTP).

The term “disease mediated by the tyrosine kinase receptor KIT” as usedherein means a disease, wherein KIT is activated by mutations or othermolecular mechanisms or overexpressed, in particular to GIST andsystemic mastocytosis, more preferably GIST.

In particular, it was found that patients suffering from GIST havingImatinib levels below about 2050 ng/mL, more specifically, Imatiniblevels below about 1100 ng/mL, show lower OR rate and shorter TTP thanpatients above that threshold.

As mentioned before, GIST belongs to the group of disease mediated bythe tyrosine kinase receptor KIT. The results obtained with the GISTpatient population described herein can be transferred directly to thewhole group of disease mediated by the tyrosine kinase receptor KIT.

The term “method of treatment” as used herein relates also to a methodof prevention of the diseases mentioned herein, i.e. the prophylacticadministration of a pharmaceutical composition comprising a KITinhibitor to healthy patients to prevent the development of the diseasesmentioned herein.

The terms “adjusting the dose” and “the dose of . . . is adjusted” asused herein preferably denote that the dose referred to is increased ordecreased. In a broader sense of the invention, the terms “adjusting thedose” and the “dose of . . . is adjusted” encompass a situation whereinthe dose remains unchanged.

Hence, in one aspect, the present invention pertains to a method oftreating a proliferative disease mediated by the tyrosine kinasereceptor KIT, in a human patient comprising the steps of

-   -   (a) administering a predetermined fixed amount of Imatinib or a        pharmaceutically acceptable salt thereof, e.g. an oral daily        dose 400 mg or 600 mg of the monomesylate salt of Imatinib, to        the human patient suffering such disease,    -   (b) collecting at least one blood sample from said patient, e.g.        within the first 12 months of treatment, e.g. within the first        30 days,    -   (c) determining the Cmin of Imatinib, and    -   (d) adjusting the dose of Imatinib or a pharmaceutically        acceptable salt thereof in a manner that a Cmin of at least 1100        ng/mL, preferably a Cmin between 1100 and about 2500 ng/mL, of        Imatinib is achieved in said patient.

In a broader sense, the present invention provides a method of treatinga proliferative disease mediated by the tyrosine kinase receptor KIT ina human patient wherein the dose of Imatinib or a pharmaceuticallyacceptable salt thereof is adjusted in a manner that a Cmin of at least1100 ng/mL, especially between about 1100 and about 2500 ng/mL,preferably a Cmin between 2050 and about 2500 ng/mL, of Imatinib ismaintained in said patient.

More specifically, the present invention relates to a method of treatingGIST in a human patient comprising the steps of

-   -   (a) administering a predetermined fixed amount of Imatinib or a        pharmaceutically acceptable salt thereof to the human GIST        patient in need thereof,    -   (b) collecting at least one blood sample from said patient, e.g.        within the first 12 months, especially the first 3 months, more        especially the first 30 days, of treatment,    -   (c) determining the plasma trough level (Cmin) of Imatinib, and    -   (d) adjusting the dose of Imatinib or a pharmaceutically        acceptable salt thereof in a manner that a Cmin of at least 1100        ng/mL, especially between about 1100 and about 2500 ng/mL,        preferably a Cmin between 2050 and about 2500 ng/mL, of Imatinib        is achieved in said patient.

In one embodiment of the present invention, the predetermined fixedamount referred to herein under step (a) represents a therapeuticallyeffective amount.

Throughout the present invention, preferably the monomesylate salt ofImatinib is used in step (a), e.g. in an oral daily dose of betweenabout 200 and about 800 mg, preferably in a daily dose of about 400 or600 mg.

Another important aspect of the present invention is the use of Imatinibor a pharmaceutically acceptable salt thereof, especially Imatinibmesylate, for the manufacture of a medicament for the treatment of GIST,wherein the dose of the pharmaceutically acceptable salt is adjusted ina manner that a Cmin of at least 1100 ng/mL, especially between about1100 and about 2500 ng/mL, preferably a Cmin between 2050 and about 2500ng/mL, of Imatinib is maintained in said patient.

The present invention is in particular of benefit for patients with GISTharboring the exon 11 KIT mutation. For the latter sub-population theOOR was 67% for patients with a Cmin below 1100 ng/mL compared to 100%for patients with a Cmin above 1100 ng/mL.

The compounds of formula I is specifically disclosed in the patentapplications U.S. Pat. No. 5,521,184, in particular in Example 21, thesubject-matter of which is hereby incorporated into the presentapplication by reference. Imatinib can also be prepared in accordancewith the processes disclosed in WO03/066613.

For the purpose of the present invention, Imatinib is preferably appliedin the form of its mono-mesylate salt. Imatinib mono-mesylate can alsobe prepared in accordance with the processes disclosed in U.S. Pat. No.6,894,051 the subject-matter of which is hereby incorporated into thepresent application by reference. Comprised are likewise thecorresponding polymorphs, e.g. crystal modifications, which aredisclosed therein.

In step (a) of the method described above, in particular a daily dose ofbetween about 200 and about 800 mg, e.g. 400 mg, of the mono-mesylatesalt of Imatinib is administered orally. Imatinib mono-mesylate can beadministered in dosage forms as described in U.S. Pat. No. 5,521,184,U.S. Pat. No. 6,894,051, US 2005-0267125 or WO2006/121941.

The collecting of a blood sample from patients required under themethods described herein can be accomplished by standard proceduresbeing state of the art. A suitable procedure for the determination ofthe plasma trough level Cmin of Imatinib andN-{5-[4-(piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-aminewas described by R. Bakhtiar R et al. in J Chromatogr B Analyt TechnolBiomed Life Sci. 2002 Mar. 5; 768(2):325-40.

SHORT DESCRIPTION OF THE FIGURES

FIG. 1 depicts the Imatinib trough distribution of the study describedin Example 1 (400 mg and 600 mg data combined).

EXAMPLE 1 Imatinib Pharmacokinetics (PK) and its Correlation withClinical Response in Patients with Unresectable/MetastaticGastrointestinal Stromal Tumor (GIST)

PURPOSE: In the randomized Phase II study (B2222), 147 pts withunresectable/metastatic GIST were randomized 1:1 to receive imatinib(IM) at 400 vs 600 mg daily. Fifty-two (52%) percent of patients arealive for >5 years, regardless of initial dose level. We report thepharmacokinetics (PK) of imatinib (IM) and the relationship between IMlevels and clinical response.

METHODS: The IM plasma levels were analyzed in a subset of patients(n=73) for whom PK data on day 1 and at steady state (Day 29) wasavailable (n=34 and 39 for 400 and 600 mg/day, respectively). The effectof patients demographics and blood chemistry parameters on IM PK wasevaluated using a population PK approach. A relationship between IMplasma exposure and clinical outcome was explored by grouping patientsinto quartiles according to IM trough levels (Cmin). The clinicaloutcome parameters evaluated include overall objective responses(OOR=CR+PR+SD), time to progression (TTP), and KIT mutations.

RESULTS: Population PK analysis showed that patients age, gender, and BWhad little effect on imatinib clearance, whereas plasma albumin and WBCcounts at baseline were identified as significant covariates. Patientswith a higher albumin level or lower WBC counts at baseline appeared tohave a higher clearance for IM. Clinical outcomes appeared to becorrelated with IM trough exposure. OOR was achieved by 12 of 18 (67%)patients in Q1 (Cmin<1110 ng/mL) compared with 29 of 36 (81%) and 16 of19 (84%) in Q2-Q3 (≧1110-<2040 ng/mL), and Q4 (≧2040 ng/mL),respectively (p=0.177 for Q1 vs Q2-Q4). The median TTP was 11.3 monthsfor patients in Q1 and over 30 months for Q2-Q4 (p=0.0029). In patientswith Exon 11 KIT mutations (n=39), the OOR was 67% for Q1 vs 100% forQ2-Q4 (p=0.009). Exon 9 KIT mutation was found in only 12 patients withCmin data, limiting the power of any correlative analyses in thissubset. The IM plasma AUC, peak concentration, and Cmin were highlycorrelated, with IM Cmin having the best correlation with response.

CONCLUSION: IM demonstrated good oral absorption, but largeinter-patient variability in IM exposure. Patients with the lowest IMtrough levels (<1100 ng/mL) show lowest OOR rate and shortest TTP.

1. A method of selectively treating a patient having GIST comprising:(a) administering a predetermined fixed dose of 400 mg or 600 mg ofimatinib mesylate to the patient; (b) assaying at least one blood samplefrom the patient within the first 12 months of treatment for a plasmatrough level (Cmin) of Imatinib mesylate; (c) thereafter, selecting thepatient for adjusting the dose of imatinib mesylate on the basis of theplasma trough level (Cmin) of less than about 1100 ng/mL in the patient;and (d) thereafter selectively adjusting the dose of Imatinib mesylatein a manner that a Cmin of between 1100 and 2500 ng/mL of Imatinibmesylate is achieved in the patient.
 2. The method according to claim 1wherein the at least one blood sample is collected within the first 3months of treatment.
 3. The method according to claim 1 wherein the atleast one blood sample is collected within the first 30 days oftreatment.
 4. The method according to claim 1 wherein the patient is aGIST patient with the Exon 11 KIT mutation.
 5. A method of predictingthe likelihood that a patient having GIST being treated with imatinibmesylate has an increased risk of lower overall objective response or ashorter time to progression and requires an adjustment of dose,comprising (a) administering a predetermined fixed dose of 400 mg or 600mg of imatinib mesylate to the patient; (b) assaying a blood samplewithin the first 12 months of treatment from the patient for thepresence of a plasma trough level (Cmin) of imatinib mesylate of lessthan about 1100 ng/mL in the patient, wherein the presence of a plasmatrough level (Cmin) of imatinib mesylate of less than about 1100 ng/mLis indicative that the patient has an increased risk of lower overallobjective response or a shorter time to progression; (c) thereafter,selecting the patient for adjusting the dose of imatinib mesylate on thebasis of the plasma trough level (Cmin) of less than about 1100 ng/mL inthe patient; and (d) thereafter selectively adjusting the dose ofImatinib mesylate in a manner that a Cmin of between 1100 and 2500 ng/mLof Imatinib mesylate is achieved in the patient.
 6. The method accordingto claim 5 wherein the at least one blood sample is collected within thefirst 3 months of treatment.
 7. The method according to claim 5 whereinthe at least one blood sample is collected within the first 30 days oftreatment.
 8. The method according to claim 5 wherein the patient is aGIST patient with the Exon 11 KIT mutation.